scholarly journals Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1877
Author(s):  
Martin Hsiu-Chu Lin ◽  
Li-Ching Chang ◽  
Chiu-Yen Chung ◽  
Wei-Chao Huang ◽  
Ming-Hsueh Lee ◽  
...  
Keyword(s):  
Cell Line ◽  
Topoisomerase Ii ◽  
Protoporphyrin Ix ◽  
Release Mechanism ◽  
Light Illumination ◽  
Disruptive Effect ◽  
Photochemical Internalization ◽  
Polyamidoamine Dendrimers ◽  
Primary Neoplasm ◽  
Human Gbm

Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a release mechanism of endocytosed therapeutics into the cytoplasm, which relies on the membrane disruptive effect of light-activated photosensitizers. In this study, phototherapy by PCI was performed on a human GBM cell-line using the topoisomerase II inhibitor etoposide (Etop) and the photosensitizer protoporphyrin IX (PpIX) loaded in nanospheres (Ns) made from generation-5 polyamidoamine dendrimers (PAMAM(G5)). The resultant formulation, Etop/PpIX-PAMAM(G5) Ns, measured 217.4 ± 2.9 nm in diameter and 40.5 ± 1.3 mV in charge. Confocal microscopy demonstrated PpIX fluorescence within the endo-lysosomal compartment, and an almost twofold increase in cellular uptake compared to free PpIX by flow cytometry. Phototherapy with 3 min and 5 min light illumination resulted in a greater extent of synergism than with co-administered Etop and PpIX; notably, antagonism was observed without light illumination. Mechanistically, significant increases in oxidative stress and apoptosis were observed with Etop/PpIX-PAMAM(G5) Ns upon 5 min of light illumination in comparison to treatment with either of the agents alone. In conclusion, simultaneous delivery and endo-lysosomal co-localization of Etop and PpIX by PAMAM(G5) Ns leads to a synergistic effect by phototherapy; in addition, the finding of antagonism without light illumination can be advantageous in lowering the dark toxicity and improving photo-selectivity.

scholarly journals Quantification of Protoporphyrin IX Accumulation in Glioblastoma Cells: A New Technique

ISRN Surgery ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Johnathan E. Lawrence ◽  
Ashish S. Patel ◽  
Richard A. Rovin ◽  
Robert J. Belton ◽  
Catherine E. Bammert ◽  
...  
Keyword(s):  
Cell Line ◽  
Fluorescent Protein ◽  
Aminolevulinic Acid ◽  
Yellow Fluorescent Protein ◽  
Protoporphyrin Ix ◽  
Cell Number ◽  
Neoplastic Tissue ◽  
A New Technique ◽  
Human Gbm

Introduction. 5-Aminolevulinic Acid (5-ALA) is a precursor of heme synthesis. A metabolite, protoporphyrin IX (PpIX), selectively accumulates in neoplastic tissue including glioblastoma. Presurgical administration of 5-ALA forms the basis of fluorescence-guided resection (FGR) of glioblastoma (GBM) tumors. However, not all gliomas accumulate sufficient quantities of PpIX to fluoresce, thus limiting the utility of FGR. We therefore developed an assay to determine cellular and pharmacological factors that impact PpIX fluorescence in GBM. This assay takes advantage of a GBM cell line engineered to express yellow fluorescent protein. Methods. The human GBM cell line U87MG was transfected with a YFP expression vector. After treatment with a series of 5-ALA doses, both PpIX and YFP fluorescence were measured. The ratio of PpIX to YFP fluorescence was calculated. Results. YFP fluorescence permitted the quantification of cell numbers and did not interfere with 5-ALA metabolism. The PpIX/YFP fluorescence ratio provided accurate relative PpIX levels, allowing for the assessment of PpIX accumulation in tissue. Conclusion. Constitutive YFP expression strongly correlates with cell number and permits PpIX quantification. Absolute PpIX fluorescence alone does not provide information regarding PpIX accumulation within the cells. Our research indicates that our PpIX/YFP ratio assay may be a promising model for in vitro 5-ALA testing and its interactions with other compounds during FGR surgery.

scholarly journals A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 12 ◽  
Author(s):  
Sylvie Berthier ◽  
Louis Larrouquère ◽  
Pierre Champelovier ◽  
Edwige Col ◽  
Christine Lefebvre ◽  
...  
Keyword(s):  
Cell Line ◽  
Sodium Selenite ◽  
Leptomeningeal Metastasis ◽  
Therapeutic Window ◽  
Patient Specific ◽  
Histone 3 ◽  
Anticancer Effects ◽  
Human Gbm ◽  
New Treatments

Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM.

scholarly journals Photodynamic Therapy Using a New Painless Light-Emitting Fabrics Device in the Treatment of Extramammary Paget Disease of the Vulva (the PAGETEX Study): Protocol for an Interventional Efficacy and Safety Trial (Preprint)

2019 ◽  
Author(s):  
Fabienne Lecomte ◽  
Elise Thecua ◽  
Laurine Ziane ◽  
Pascal Deleporte ◽  
Alain Duhamel ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Disease Control ◽  
Medical Device ◽  
Red Light ◽  
Protoporphyrin Ix ◽  
University Hospital ◽  
Disease Control Rate ◽  
Light Illumination ◽  
Efficacy And Safety ◽  
Paget Disease

BACKGROUND Extramammary Paget disease of the vulva (EMPV) is a rare skin disorder commonly seen in postmenopausal Caucasian females that appears clinically as red, eczematous, pruriginous, and sometimes painful lesions. Although most cases are noninvasive, EMPV may be associated with an underlying or distant adenocarcinoma. EMPV has a chronic and relapsing course. The reference treatment is based on local surgical excision with negative margins. However, disease frequently extends far from the visible lesion, and surgical margins are frequently positive. Topical photodynamic therapy (PDT) is an established treatment modality for various dermatooncologic conditions. For example, red light irradiation with the Aktilite CL 128 and Metvixia (Galderma SA) as a photosensitizing molecule is a conventional protocol approved and widely used in Europe for PDT treatment of actinic keratosis, but this treatment is not yet widely used for EMPV because it has never clearly been demonstrated and is very painful. OBJECTIVE The aim of the study is to investigate the efficacy and safety relating to the medical device PAGETEX as a new painless PDT device using Metvixia in the treatment of vulvar Paget disease. The primary end point is the disease control rate at 3 months in 30% of the patients included, defined as stability, partial response, or total response, considering the extent of the lesion. Secondary end points are the disease control rate at 6 months, patient quality of life, level of pain experienced by the patient at each PDT session, severity of erythema, presence of protoporphyrin IX in Paget cells after each PDT session, and overall satisfaction level of the patient. METHODS The trial is an interventional, exploratory, simple group, nonrandomized, and single center (Lille University Hospital) study. Twenty-four patients will be included according to Simon’s optimal plan. Therapeutic procedure is based on a cycle of two PDT sessions with the PAGETEX medical device at 15-day intervals (Metvixia incubation during 30 minutes and 635 nm red light illumination with a low irradiance for 2 hours and 30 minutes for a total fluence of 12 J/cm²). At the assessment session, 3 months after inclusion, if the control of the disease is partial or null, the patient will complete another cycle of two PDT sessions. A final evaluation will be performed in all patients at 6 months. Analyses will be performed using SAS version 9.4 software (SAS Institute Inc). The characteristics of the patients at baseline will be described; qualitative variables will be described by numbers and percentages, and quantitative variables will be described either by the mean and standard deviation for Gaussian distribution or by the median and interquartile range (ie, 25th and 75th percentiles). The normality of the distributions will be tested by a Shapiro-Wilk test and checked graphically by histograms. RESULTS First patient was included in September 2019 and clinical investigations are planned until August 2022. The final results of this study are expected to be available in January 2023. CONCLUSIONS This clinical trial aims to evaluate the efficacy and safety of a new PDT protocol for the treatment of EMPV. The PAGETEX device could become the treatment of choice if it is effective, painless, and easy to implement and use in hospitals. CLINICALTRIAL ClinicalTrials.gov NCT03713203; https://clinicaltrials.gov/ct2/show/NCT03713203 INTERNATIONAL REGISTERED REPORT PRR1-10.2196/15026

scholarly journals Photodynamic Therapy Using a New Painless Light-Emitting Fabrics Device in the Treatment of Extramammary Paget Disease of the Vulva (the PAGETEX Study): Protocol for an Interventional Efficacy and Safety Trial

10.2196/15026 ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. e15026 ◽  
Author(s):  
Fabienne Lecomte ◽  
Elise Thecua ◽  
Laurine Ziane ◽  
Pascal Deleporte ◽  
Alain Duhamel ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Disease Control ◽  
Medical Device ◽  
Red Light ◽  
Protoporphyrin Ix ◽  
University Hospital ◽  
Disease Control Rate ◽  
Light Illumination ◽  
Efficacy And Safety ◽  
Paget Disease

Background Extramammary Paget disease of the vulva (EMPV) is a rare skin disorder commonly seen in postmenopausal Caucasian females that appears clinically as red, eczematous, pruriginous, and sometimes painful lesions. Although most cases are noninvasive, EMPV may be associated with an underlying or distant adenocarcinoma. EMPV has a chronic and relapsing course. The reference treatment is based on local surgical excision with negative margins. However, disease frequently extends far from the visible lesion, and surgical margins are frequently positive. Topical photodynamic therapy (PDT) is an established treatment modality for various dermatooncologic conditions. For example, red light irradiation with the Aktilite CL 128 and Metvixia (Galderma SA) as a photosensitizing molecule is a conventional protocol approved and widely used in Europe for PDT treatment of actinic keratosis, but this treatment is not yet widely used for EMPV because it has never clearly been demonstrated and is very painful. Objective The aim of the study is to investigate the efficacy and safety relating to the medical device PAGETEX as a new painless PDT device using Metvixia in the treatment of vulvar Paget disease. The primary end point is the disease control rate at 3 months in 30% of the patients included, defined as stability, partial response, or total response, considering the extent of the lesion. Secondary end points are the disease control rate at 6 months, patient quality of life, level of pain experienced by the patient at each PDT session, severity of erythema, presence of protoporphyrin IX in Paget cells after each PDT session, and overall satisfaction level of the patient. Methods The trial is an interventional, exploratory, simple group, nonrandomized, and single center (Lille University Hospital) study. Twenty-four patients will be included according to Simon’s optimal plan. Therapeutic procedure is based on a cycle of two PDT sessions with the PAGETEX medical device at 15-day intervals (Metvixia incubation during 30 minutes and 635 nm red light illumination with a low irradiance for 2 hours and 30 minutes for a total fluence of 12 J/cm²). At the assessment session, 3 months after inclusion, if the control of the disease is partial or null, the patient will complete another cycle of two PDT sessions. A final evaluation will be performed in all patients at 6 months. Analyses will be performed using SAS version 9.4 software (SAS Institute Inc). The characteristics of the patients at baseline will be described; qualitative variables will be described by numbers and percentages, and quantitative variables will be described either by the mean and standard deviation for Gaussian distribution or by the median and interquartile range (ie, 25th and 75th percentiles). The normality of the distributions will be tested by a Shapiro-Wilk test and checked graphically by histograms. Results First patient was included in September 2019 and clinical investigations are planned until August 2022. The final results of this study are expected to be available in January 2023. Conclusions This clinical trial aims to evaluate the efficacy and safety of a new PDT protocol for the treatment of EMPV. The PAGETEX device could become the treatment of choice if it is effective, painless, and easy to implement and use in hospitals. Trial Registration ClinicalTrials.gov NCT03713203; https://clinicaltrials.gov/ct2/show/NCT03713203 International Registered Report Identifier (IRRID) PRR1-10.2196/15026

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